WHAT MAJOR ADVANCES can we expect in the next ten years? As Yogi Berra said in his unique way, “Predictions are difficult, particularly about the future.” But some things are clear. Personalized medicine is here to stay. It is going to spread as people acquire and share their digital data; it is going to become more accurate as big data analyses and technological advances lead to further improvements in our understanding of disease; it is going to be expanded into maintaining health in addition to identifying and treating disease; it is going to democratize medical care in the sense that very sophisticated diagnostics will become generally available to consumers; it is going to lead to enormous new industries aimed at maintaining wellness and treating potential rather than actual disease; it is going to completely disrupt current medical practices; and it is going to pose considerable ethical and social dilemmas. Many of these changes will arise from four areas where research activity is particularly intense: advances in gene therapy, improved understanding of brain function, investigations into the biology of aging, and the use of molecular-level medicine to maintain wellness.
Personalized medicine and gene therapy go hand in hand. The idea behind gene therapy is that if we can detect the genetic basis of a disease, that disease can be treated by inserting new genes into your genome in place of defective ones. The reasoning is straightforward: if a gene in your genome contains a mutation, leading to a protein that doesn’t work properly, why not insert a functional copy of the gene into the genome? Putting this idea into practice has been somewhat difficult, however. For obvious reasons, your body has evolved elaborate defense mechanisms to prevent any invader from injecting its DNA or RNA into your genome.
Given that evolution has produced viruses that can insert their genome into the genome of target cells as part of the infective process, scientists have made great efforts to use viruses to replace defective genes in cells with functional versions. First attempts used modified viruses, containing the therapeutic gene, which could not be infective (that is, the virus could not replicate itself). However, the virus inserted the new gene into the genome of the target cell at random locations. This development proved risky because random insertion of DNA into your genome can potentially perturb expression of other genes and lead to new problems. Something like this process seems to have happened in gene-therapy trials in the early 2000s to treat children suffering from an immune disorder called X-linked severe combined immunodeficiency (X-SCID). X-SCID is often referred to as “bubble boy” disease because children suffering from this disease are extremely susceptible to infection, sometimes requiring a sterile chamber environment to avoid bacteria or viruses. Sadly, some of the children who received gene therapy for X-SCID to replace the defective gene developed leukemia a few years later. Researchers believe the random insertion of the gene activated an oncogene — a gene that can cause cancer.1
Another problem is that your immune system is programmed to recognize invading viruses and eliminate them from your body and also to kill cells that become infected by a virus. These immune reactions can be so intense that they are sometimes lethal. As discussed in a New York Times article published in 1999, Jesse Gelsinger suffered from ornithine transcarbamylase (OTC) deficiency, a rare genetic disorder that results in a buildup of ammonia due to incomplete breakdown of proteins.2 In Jesse’s case, this was controlled with a low-protein diet and drugs — thirty-two pills a day. In a quest to correct his OTC deficiency, Jesse was injected with a modified cold virus that contained the gene for OTC. The subsequent immune response was so strong that Jesse suffered multiple organ failure and died four days later. That was a black day not only for Jesse but also for gene therapy. Further development was halted for almost ten years.
These and other failures have led to some cynicism about the future of gene therapy for treating hereditary diseases such as Gaucher’s or Huntington’s, or diseases such as cancer. Claims that effective gene therapies are just around the corner and will provide a new method of curing hitherto incurable diseases are often dismissed as hyperbole. When an early version of the human genome sequence was announced in June 2000, Bill Clinton stated, “Genome science will revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases. In coming years, doctors increasingly will be able to cure diseases like Alzheimer’s, Parkinson’s, diabetes and cancer by attacking their genetic roots . . . In fact, it is now conceivable that our children’s children will know the term cancer only as a constellation of stars.”3 It hasn’t quite turned out that way — yet. But there are signs of progress.
So what’s changing now? The first gene-therapy drug was approved for human use by the European Medicines Agency in 2012: Glybera,4 a drug to treat lipoprotein lipase (LPL) deficiency, a very rare (one in a million) inherited disease that can lead to severe pancreatitis. The delivery vehicle used is a virus that does not induce a strong immune response, known as adeno-associated virus (AAV), which is injected into the thigh muscle. The treatment has been shown to reduce lipid levels in the blood and prevent attacks of pancreatitis for up to two years. This success has led to other AAV-based gene therapies that are in development, including treatments for hemophilia, retinal degeneration, Parkinson’s disease, and muscular dystrophy. Viruses are also proving useful for introducing genes into immune cells to enhance recognition of tumor cells, as discussed in the previous chapter.
As detailed in chapter 5, a form of gene therapy using antisense or siRNA oligonucleotides (short pieces of DNA or RNA, usually about twenty bases long) to silence target genes associated with disease is also increasingly successful. Isis Pharmaceuticals, a biotechnology company based in California, received FDA approval for Kynamro — a drug to treat high cholesterol by inhibiting production of a protein required to make LDL.5 In addition, Alnylam Pharmaceuticals, a biotechnology company based in Boston, is developing a siRNA drug called patisiran which entered Phase III clinical trials in late 2013.6 Patisiran silences a gene called transthyretin (TTR); mutations in the TTR gene cause defective TTR proteins to be made that can form insoluble amyloid plaques of denatured protein in heart and nerve tissue, causing heart failure and a progressive loss of sensation in the hands and feet. The only current treatment is a liver transplant. It is anticipated that the lower levels of TTR protein in the blood induced by patisiran will lead to reduced deposition of amyloid plaques, perhaps causing previously formed plaques to dissolve. There are many other DNA- or RNA-based drugs in clinical development, and there is good reason to believe that they are going to be very effective.
So the future of gene therapy is increasingly bright. A particularly exciting development is that technology for manipulating your DNA is evolving rapidly. Nanosurgery on your DNA to correct defects may soon be an option. So-called CRISPR (clustered regularly interspersed short palindromic repeats) technology can be used to cut out the DNA of defective genes and insert the correct sequence. As Feng Zhang, a professor at MIT says, “We can go into the native genome, the natural DNA in the cell, and then make a modification in the genome to correct deleterious mutations.”7 This is incredible. Already this technique has been used to cure mice of genetic defects leading to cataracts and to insert DNA into the genome of stem cells to correct the cystic fibrosis gene. Other researchers are using the technique to delete a gene known as PCSK9, which can dramatically lower cholesterol levels, potentially providing a “vaccine” against heart disease.8 So gene therapy is experiencing a remarkable renaissance, and many personalized, precise, and safe gene medicines are marching their way towards everyday clinical use.
Personalized medicine and your brain: that’s a big one. Let’s start with dementia, forgetting who you are. It doesn’t get more personal than that. Dementia is a disease of old age, and its incidence doubles roughly every five years after the age of sixty-five. The prevalence of dementia in late old age is extreme, rising from 12 percent at age eighty to 22 percent for men and 30 percent for women at age ninety.9 So you might want to live for a long time, but you’d better hope there’s a cure for Alzheimer’s disease and other disorders that cause cognitive impairment by the time you pass eighty. (Hopefully, something better than weight lifting.) You’ll also need to save a lot of money: in the U.S. in 2010, the cost for care of demented people was in the range of $200 billion, taking into account the cost of assisted living.10 This is not cheap: twenty-four-hour care can easily cost $100,000 a year. Your children may love you, but if they are paying, they may think wistfully of the days, possibly mythological, when the Inuit could ship their infirm elders out to sea on the nearest ice floe.
How about personalized medicine and your mental health? According to the National Alliance on Mental Illness, nearly one in two people in the U.S. will suffer from depression, anxiety disorders,11 or another mental health problem at some point in their life, and about one in seventeen currently has a serious mental illness. Costs due to mental illness run in excess of $100 billion per year in lost productivity; in addition, schools have to offer special education, the court system is saturated with people who have mental disorders, and mental health problems culminating in suicide are a leading cause of death in younger people.
And then we have all the other problems that are brain related: Huntington’s, Parkinson’s, epilepsy, schizophrenia, autism, meningitis, stroke, concussion, brain tumors — the list goes on and on. And we are really not very good at treating any of these conditions. So is personalized medicine going to do anything about it? This is a tough question to answer. So far, personalized medicine for the brain is limited to attempts to tailor antidepressants and other drugs used to treat mental problems to avoid adverse drug reactions. Overall the field is fundamentally limited by a lack of understanding of how the brain works. So the question becomes, are we going to see improvements in our understanding of how the brain operates over the next decade, which can then be expected to lead to individualized solutions? The answer to that is, “Probably.”
The central problem here is relating the biology of the brain to behavior. Activity in various parts of the brain can be observed in response to various stimuli using techniques such as functional magnetic resonance imaging (fMRI). However, despite many advances, the spatial resolution is still relatively poor. Each pixel of the fMRI image corresponds to at least 100,000 neurons; the firing of individual neurons cannot be detected. But it is crucial to detect these individual events. The thoughts you have are likely due to “emergent behavior” resulting from the simultaneous firing of thousands of neurons in your head. The term emergent behavior, in this case, refers to behavior that cannot be predicted by analysis of any one neuron; it is many neurons interacting together that enable your brain to think, act, and dream. The potential for emergent behavior in the brain is huge. There are approximately 11 billion neurons in your brain, and each of these has on average 7,000 connections with other neurons. Neurons are connected to each other by synapses that transmit electrical signals from one neuron to the next, so there are approximately 100 trillion individual synapses that can be firing at any one time. In the language of omics, this is called your connectome. It is a daunting task to map the connectome and correlate thousands, tens of thousands, or even greater numbers of synapses firing at once with your ability to remember, feel, see, and talk.
But there are many wild and wonderful new technologies that are attempting to do just that. Currently in development are nano-size sensors to detect electrical impulses when implanted deep in the brain, techniques to image the brain according to the voltage across the neural membrane (which corresponds to nerve firing), as well as optogenetics — inserting genes into neurons that respond to light by causing ions to flow across neural membranes, thus turning neurons on or off. The information-processing demands are huge. As Rafael Yuste and George Church indicate in an article in Scientific American in 2014,12 imaging the activity of all the neurons in a mouse brain could generate 300 petabytes of data in an hour. Compare this to storing your genome, a mere 800 gigabytes — about 400,000 times less data. Moving to the human brain will require considerably more data generation, storage, and analysis. But just as it was impossible for Watson and Crick to imagine sequencing the whole human genome in 1954, it would be unwise for us to say this kind of imaging can’t happen within the next ten years.
So we can see the day coming when, thanks to one imaging technique or another, rudimentary maps of the brain activity associated with our moods, behavior, and actions will be achieved. It is not hard to envision that this will lead to some very personalized therapies, be they for depression, addiction, schizophrenia, or a host of other disorders, by simply interfering with the activity pattern associated with extremes of mood and behavior. Equally, of course, it could go the other way, with customers paying to be induced into a constant state of orgasm or other forms of ecstatic pleasure. Whether or not such therapies or indulgences will be available in ten years is certainly arguable, but it is likely that we will start to see the outlines of how to get there.
What about aging and personalized medicine? A focus on the elderly and treating aging as a potentially preventable disease makes sense in a lot of ways: the elderly consume a disproportionate share of the health-care budget, in large part because of chronic conditions such as dementia, arthritis, diabetes, and cardiovascular disease, to say nothing of more acute diseases such as cancer. The costs are huge: people aged sixty-five and over made up around 13 percent of the U.S. population in 2002, but they consumed 36 percent of total U.S. personal health-care expenses.13 In Canada, the current number is closer to 44 percent.14 These costs are only going to increase as baby boomers cross the sixty-five-year-old threshold. Some estimates suggest a doubling in costs for the elderly by 2030. Whatever the numbers, the situation is clearly not sustainable.
You are probably not used to thinking that aging could be seen as a disease, and for that matter, neither is the FDA. It doesn’t acknowledge aging to be a treatable condition. And promoting that concept, with its connotations of seeking immortality, certainly puts you in some fairly flaky company. But research aimed at understanding and treating aging processes has gained respectability and has generated some credible approaches.
The telomere story, for example, is becoming increasingly persuasive. In the early 1960s, Leonard Hayflick, a professor at Stanford University, discovered that when human fetal cells were cultivated in a medium that contained all the essential ingredients to keep cells happy, they divided approximately fifty times, then stopped and entered a period of senescence. Senescence means that the cells became “old” and either committed suicide by a process called apoptosis or remained alive but exhibited different gene-expression profiles from their precursors, indicating altered, presumably reduced, functional capabilities. In the 1970s, it was discovered that the ends of the DNA strands in chromosomes contain regular repeats of DNA sequences, dubbed telomeres, and that when a cell divides, it does not completely replace these DNA repeats; in other words, the telomere gets shorter every time a cell divides. This finding was finally used to explain the “Hayflick limit”: if the telomeres become short enough, then the cells can no longer divide.
As a result, the study of telomeres has become a central feature of aging research because it suggests that the reason you get old and die is because your telomeres get shorter as you get older, resulting in more senescent cells that don’t function very well. And there seems to be some truth in that. Senescent cells accumulate with increased age in species ranging from mice to humans. Suppressing senescent cells in mice has been shown to improve their health. You may have heard of the disorder known as progeria. Children suffering from this condition undergo premature aging and die, essentially of old age, in their early teens. These children have a mutation in a gene that results in rapid cell senescence.
Shorter telomeres in humans are associated with many age-related diseases including cancer, cardiovascular disease, and dementia. But would immortality be possible if you maintain telomere length? It’s not out of the question. In studies that led to a Nobel Prize in 2009, a protein called telomerase was identified that can lengthen the telomere to let cells keep on dividing. This discovery was followed by characterization of a type of worm that is, to all intents and purposes, immortal.15 As Dr. Aziz Aboobaker of the University of Nottingham explains, “Planarian worms appear to [be able to] regenerate indefinitely by growing new muscles, skin, guts and even entire brains over and over again.” So what is going on? As Aboobaker states, “Usually when stem cells divide — to heal wounds, or during reproduction or for growth — they start to show signs of aging. Our aging skin is perhaps the most visible example of this effect. Planarian worms and their stem cells are somehow able to avoid the aging process and to keep their cells dividing.” The Nottingham team identified a planarian version of the gene coding for telomerase and found that at least one species of Planarian worms dramatically increase the activity of the gene that codes for telomerase when they regenerate, allowing stem cells to maintain their telomeres as they divide to replace missing tissues.
While all cells contain the gene for telomerase, it is expressed at low levels (or not at all) in most cells. It is expressed in a subset of blood cells called peripheral blood mononuclear cells (PBMC), and its activity can be measured using a relatively simple blood test; alternatively, telomere length can also be measured in various tissues. Efforts have been made to find drugs that activate telomerase, and indeed small-molecule activators of telomerase have been identified and shown in early studies to improve the apparent health status of mice. Interestingly, statins to inhibit cholesterol synthesis seem to have a telomerase-activating effect. There is evidence that growth hormones, such as human growth hormone, also activate telomerase. Meditation and adherence to the Mediterranean diet have also been associated with lengthening telomeres. A big factor is exercise, as there is growing evidence that it plays a direct role in activating telomerase — in other words, in keeping you younger.
The observation that exercise results in longer telomeres could explain the remarkable benefits of exercise in almost every area of human health. Exercise is an amazing drug; it reduces the risk of colon cancer by at least 25 percent, breast cancer by 20 percent to 40 percent, lung cancer (in smokers) by 35 percent, and skin cancer (in mice) by over 60 percent.16 A statement from the American Heart Association in 2003 says, “Habitual physical activity prevents the development of coronary artery disease and reduces symptoms in patients with established cardiovascular disease.”17 There is also evidence that exercise reduces the risk of other chronic diseases, including type 2 diabetes, osteoporosis, obesity, and depression. It reduces blood pressure. In fact, what doesn’t exercise do? It seems it keeps your telomeres long as well, which may explain some of its “magic bullet” qualities. In an article published in 2008, Tim Spector and associates at King’s College London examined the effects of exercise in 2,400 sets of identical twins, and the findings were unambiguous:18
People who did a moderate amount of exercise — about 100 minutes a week of an activity such as tennis, swimming or running — had telomeres that on average looked like those of someone about five or six years younger than those who did the least — about 16 minutes a week. Those who did the most — doing about three hours a week of moderate to vigorous activity — had telomeres that appeared to be about nine years younger than those who did the least. As the amount of exercise increased, the telomere length increased.
A potential downside associated with telomerase activation is that approximately 90 percent of tumor cells exhibit telomerase activity, which is consistent with their ability to divide indefinitely, so increasing cancer risk could be a concern — although it is clear that exercise does not increase cancer risk; rather, the reverse. In any event, it is likely that we will soon discover ways to prevent the accumulation of the senescent cells that makes us old. This advance could well happen within ten years. After all, the fundamental miracle is that you were born and grew to be what you are; correcting defects that appear is really just a matter of understanding the biology at the molecular level and using this understanding to reengineer tissues as they age. In the meantime, it might be a good idea to hit the gym.
Other biomarker tests that correlate with aging are also appearing. One type of epigenetic modification occurs when chemical tags known as methyl groups are attached to specific regions of genomic DNA: production of proteins from genes in those regions is inhibited. Steve Horvath of the University of California examined the relationship between DNA methylation and aging in brain, breast, skin, colon, kidney, liver, lung, and heart tissue taken from people ranging in age from newborns to 101 years old. He found 353 DNA sites where methyl groups increased or decreased with age and developed a predictive algorithm based on this data. As reported in Genome Biology in 2013, he found that the computed age based on DNA methylation closely predicted the age of numerous tissues to within just a few years.19 In embryonic and induced pluripotent stem cells, the DNA methylation age proved to be near zero. Horvath says, “My goal in inventing this age-predictive tool is to help scientists improve their understanding of what speeds up and slows down the human aging process.”20 Horvath plans to examine whether DNA methylation is only a marker of aging or itself affects aging.
The onslaught on aging is gathering momentum. The observation noted in chapter 3 that the blood of young mice led to rejuvenation of the hearts of older mice has now been confirmed and extended to other organs. In three separate studies published in Science and Nature in early 2014, scientists reported that they reversed aging in the muscles and brains of old mice by running the blood of young mice — or the protein GDF11 — through their veins.21 Researchers at Harvard found that treated mice could run longer on a treadmill and had more branching blood vessels in their brains than untreated mice. GDF11 is also found in human blood. Will the observations in mice extend to people? We will certainly find out in the next ten years.
Craig Venter of genome-sequencing fame has also joined the anti-aging bandwagon, raising more than $70 million in early 2014 to start a company called Human Longevity, Inc. “Our goal is to make 100-years-old the new 60,” said Peter Diamandis, CEO.22 The company aims to scan the DNA of as many as 100,000 people a year to create a massive database that will be complemented by microbiomic, proteomic, and metabolomic data. Correlation of this data with age and presence or absence of disease is anticipated to lead to new tests and therapies that can help extend healthy human life.
Google is entering the longevity arena by forming a company called Calico.23 Rumors have it that an objective of Calico is to extend the life of people born in the last twenty years by as much as a hundred years. Google, of course, is going to have the advantage of huge data-mining capabilities. As an early investor in 23andMe, it also has access to extensive genomic data for analysis. Other companies with similar aims are springing up with increasing frequency, backed by enormous amounts of money from private investors. As Steven Edwards, a policy analyst at the American Association for the Advancement of Science, states, “For better or worse, the practice of science in the 21st century is becoming shaped less by national priorities or by peer-review groups and more by the particular preferences of individuals with huge amounts of money.”24 And their impact seems likely to grow, given the relative decline in publicly funded research and the enormous wealth of these private individuals. A New York Times analysis shows that the forty or so richest science donors who have signed a pledge to give most of their fortunes to charity have assets surpassing a quarter-trillion dollars. It is not irrational to suggest that a large proportion of this money will be invested in efforts to extend the human life span, particularly the life span of the wealthy individual.
What do the next ten years hold in terms of personalized medicine and preventive care to maintain wellness? This area is set for explosive growth. Americans spend over $30 billion a year on natural health products that have no proven value,25 and somewhat more on “functional foods” (such as probiotic yogurt) that may have benefits, but you often don’t know for sure. You can imagine what consumers would spend if they knew that the food and food supplements they purchased were actually doing some good. More importantly, it would be good to know which drugs will work for you and be compatible with you. Adverse drug reactions result in approximately 10 million hospital visits per year in the U.S. and cost nearly $200 billion. Some programs just starting now will address all these issues and much, much more. One of the first is being organized by Leroy Hood of the Institute for Systems Biology in Seattle.26 Hood is a pioneer and an extremely effective proselytizer for personalized medicine, and his study may well become a premier example of preventive medicine in the future.
If you want to know everything you can about yourself, Hood’s study is for you. Participants will be extensively examined both at the molecular level and at macroscopic levels using the latest methods made possible through omic and remote-sensing technology. Their genomes will be sequenced and analyzed to identify genetic risk factors for disease and for drug compatibility. Their physical activity, heart rate, and sleep patterns will be continually monitored to ascertain health status. And every three months, microbial species in the colon, metabolites such as blood glucose (a biomarker for diabetes) and creatinine (a biomarker for kidney function), and about 100 proteins that will indicate the health of your liver, lungs, brain, and heart will be analyzed and monitored for transitions from health to disease.
Eventually, Hood plans to enroll 100,000 people, generate personal big-data clouds for all these individuals and follow them for thirty or more years. It’s a measure of Hood’s drive and passion, not to mention optimism, that at age seventy-five he is embarking on a study that could take thirty years to reach maturity. Transitions to common diseases such as cardiovascular diseases, cancer, and neurological diseases will occur among the test participants over this period, and by analyzing this data, Hood hopes to develop predictive models to delineate early biomarkers for disease, allowing early intervention before the disease becomes life threatening, as well as ways of detecting the resolution of disease as the participant’s biomarkers return to normal. These biomarkers should also allow you to rapidly determine whether the therapy you are using to treat whatever disease you may have is, in fact, working.
All this data and subsequent analysis will lead to actionable possibilities. As Hood writes, “An actionable possibility is a feature for an individual that, if corrected, could improve wellness or avoid disease. A friend was told that he had early onset osteoporosis in his mid-30s — a disease that potentially could confine him to a wheel chair for the rest of his life. After genetic analysis, he discovered that he had a defective ability to absorb calcium. He took 20 times the normal amount of calcium for several years and returned his bone structure to normal and after about 12 years continues to remain normal on this regimen. Thus this genetic defect is actionable in that it can be corrected by taking more calcium.”
Another example Hood gives concerns a physicist who began to lose interest in his work and had difficulty concentrating. As the problem continued for a considerable time, he underwent blood screening. It turned out that he was severely deficient in iron. Within days after replacement therapy, he returned to normal and resumed his former life with his typical enthusiasm. Hood believes that we have 300 to 500 of these actionable genetic variants and that many of them arise from nutritional deficiencies that can be readily corrected.
At present, the practice of medicine, particularly in hospitals, is focused on treating disease rather than preventing it. Public-health medicine and primary-care efforts by general practitioners do emphasize preventive care but mainly through encouraging exercise and healthy diets, as well as smoking cessation. This blunderbuss approach is in stark contrast to the precise, individualized information gained and used in Hood’s project. The combined data generated by Hood’s and other wellness initiatives will be of enormous value, as it will establish a database that can be mined to create new biomarker tests of health and disease and offer new information about the effects of environment and diet on our physical and mental states, and will also create completely new industries aimed at maintaining health and extending life. For example, data providing evidence that you’re trending towards disease will lead to new therapies aimed at correcting these trends rather than treating the disease itself.
What else can we expect over the next ten years? One thing is certain: we are going to make new biological discoveries that will upset present notions about how our cells and our bodies work. The functional roles of the 98 percent of your genome that does not code for genes are an area of intense research, and it appears that a large proportion of the noncoding region of the genome plays regulatory roles for gene expression. Furthermore, approximately 90 percent of disease-associated mutations are in noncoding regions, and finding out how those mutations influence disease is likely to lead to new treatment modalities.
Other surprises are in store as we identify new biomarkers associated with disease or wellness. As discussed previously, diagnostics that use genomic, proteomic, and other data are well on their way to being of practical use. Recent studies show that the small bits of RNA called microRNA (miRNA) in body fluids such as blood can also have important diagnostic uses, such as early detection of cancer. For example, pancreatic cancer is difficult to detect until it is too late. Nicolai Schultz of the Herlev Hospital in Copenhagen has identified a panel of miRNAs in the blood that appear to be diagnostic for the presence of pancreatic cancer.27 As Schultz states, “The test could diagnose more patients with pancreatic cancer, some of them at an early stage, and thus have a potential to increase the number of patients that can be operated on and possibly cured.” Other studies suggest that miRNA screens could be used to detect ovarian cancer — another cancer that is often detected too late for effective therapy.
The potential utility of miRNA diagnostics is not limited to cancer. Eckart Meese and Andreas Keller at Saarland University have shown that by measuring the levels of twelve types of miRNA in the blood, they could predict, with 93 percent accuracy, whether or not an individual had Alzheimer’s disease.28 “At this point of our research, we are only at the beginning of a biological understanding of the miRNA pattern identified,” they said in an interview. “Our results make us confident that miRNA signatures can likely play a role in the future diagnosis of Alzheimer’s disease.” Because Alzheimer’s disease starts years before cognitive decline begins, a test for the early stages of the disease could allow early intervention, before irreparable damage is done. It is also possible that such tests could be useful to assay whether Alzheimer therapeutics are actually working by determining whether the miRNA levels revert to a normal profile.
We can expect other new types of diagnostics as well. There are stories of dogs alerting their owners to diseases such as lung cancer and breast cancer. These animals may have an ability to detect volatile organic compounds (VOCs), which can be diagnostic for cancer. Considerable work is being done to ascertain the utility of VOCs as biomarkers of disease. Peter Mazzone and his team at the Cleveland Clinic have developed a breath test for lung cancer.29 Mazzone’s test, the colorimetric sensor assay, consists of an array of pigments that change color when they come in contact with certain VOCs, and it is sensitive enough to distinguish between different types of lung cancer, including non-small cell cancer, adenocarcinoma, and squamous cell carcinoma.
New approaches to disease detection will come from unlikely sources. Pancreatic cancer, which killed Apple founder Steve Jobs, has a five-year survival rate of only 15 percent, in part because we are unable to detect early-stage disease. Fourteen-year-old Jack Andraka developed a low-cost paper strip–based test for mesothelin, a pancreatic cancer biomarker.30 The test uses carbon nanotubes — tiny cylinders made with carbon sheets an atom thick — coated with an antibody that binds to the mesothelin. When this protein latches on to the nanotube, it changes the separation between the carbon nanotubes in a way that also changes their electrical conductivity. His invention won him the $75,000 Gordon E. Moore Award, the grand prize of the Intel International Science and Engineering Fair in 2012, when he was fifteen.
New molecular-level diagnostics for infectious disease will also appear. For example, antibiotic resistance is a major health threat, with 23,000 Americans dying from resistant strains of infections each year. A key contributor to resistance is the overuse of antibiotics, particularly to treat viral infections, which antibiotics cannot affect. Because it can be hard to tell the difference between a viral and a bacterial infection, physicians often write prescriptions for antibiotics, just in case. In many countries, patients buy them over the counter, just to make sure. At Duke University, Geoffrey Ginsburg and his team have detected different gene-expression profiles in response to viral infections as opposed to bacterial infections.31 Ginsburg’s test boasts a 90 percent accuracy rate in identifying a viral respiratory infection and can return results within twelve hours, compared with the days that traditional test results take.
Other new advances, especially for treating cancer, are likely as we achieve greater understanding and control of the immune system. As detailed in chapter 5, great advances are being made by manipulating the immune system to treat blood cancers such as leukemias, and it is likely that in the next decade, similar methods will be developed to treat solid cancers such as lung and breast cancer. Creating these treatments will require the development of ways to defeat the ability of these cancer cells to suppress the immune system, but efforts are under way to do just that. At Stanford University, Irving Weissman and his team have developed an antibody that prompts the immune system to recognize and attack cancer cells.32 The ability of cancer cells to avoid recognition by the immune system comes partly from a protein called CD47, which sends a “don’t eat me” signal to macrophages — the white blood cells that destroy pathogenic invaders. By blocking CD47, Weissman’s antibody allows the macrophages to attack the cancer cells and in turn mobilize the body’s entire immune response against the cancer. What’s exciting about Weissman’s work is that CD47 isn’t specific to any particular cancer: “What we’ve shown is that CD47 isn’t just important on leukemias and lymphomas,” says Weissman. “It’s on every single human primary tumor that we tested.”
Surprises are definitely going to come as we understand more about the brain and how it functions. In 2013, Michael McConnell at the Salk Institute for Biological Studies discovered that our neurons vary to a striking degree: as many as 40 percent of neurons exhibit large chunks of deleted or duplicated DNA (known as copy number variants, or CNVs) as compared to a “standard” neuron.33 As McConnell told ScienceDaily, “The thing about neurons is that, unlike skin cells, they don’t turn over, and they interact with each other. They form these big complex circuits, where one cell that has CNVs that make it different can potentially have network-wide influence in a brain.” Spontaneous CNVs have been linked with schizophrenia and autism, so developing an understanding of how CNVs form could clarify origins of mental health disorders.
As you may already have come to appreciate, technology never ends, and we are going to get additional surprises as new technologies come online. Three-dimensional (3D) printing, now in its infancy, is going to have a profound impact. Its applications couldn’t be more personalized. In March 2013, a man in the northeastern U.S. had 75 percent of his skull replaced by a 3D-printed polymer implant, designed with the help of CT scans.34 Using an inkjet-type device, Keith Martin and his team at the University of Cambridge have successfully layered living retinal cells.35 Said Martin, “This is the first time that cells from the adult central nervous system have been successfully printed. We’ve demonstrated that you can take cells from the retina and you can effectively separate them out. We can print those cells out in any pattern we like, and we’ve shown that those cells can survive and thrive.” Although this research is still in its early stages, it points to the potential for sculpted tissues customized to the patient. Martin suggests that these techniques will lead to eventual cures for macular degeneration and glaucoma, the two leading causes of blindness in developed countries. It is not hard to imagine the combination of 3D printing techniques and stem cell technology leading to an ability to grow organs outside your body, for subsequent implantation.
Advances in stem cell technology will also lead to new drugs. For example, Gabsang Lee of the Johns Hopkins Institute for Cell Engineering extracted skin cells from an individual suffering from Riley-Day syndrome, a rare genetic disorder affecting sensory nerves.36 People with Riley-Day have frequent vomiting crises, problems with speech and movement, difficulty swallowing, inappropriate perception of heat, pain, and taste, unstable blood pressure, and gastrointestinal problems. Using the induced pluripotent stem cell approach, Lee and his team coaxed those skin cells into becoming neurons. They were then able to screen thousands of drugs to see which ones would make the neurons express higher levels of the genes that were not produced in adequate amounts. “Because we could study the nerve cells directly, we could for the first time see exactly what was going wrong in this disease,” said Lee. They ultimately identified a compound that shows promise for stopping or reversing Riley-Day syndrome.
Personalized approaches to health care are also going to be extended to more tailored treatment of the very young and the very old. As noted by the Institute of Medicine, “The majority of drugs prescribed for children — 50 to 75 percent — have not been tested in pediatric populations.”37 In essence, we treat children as if they are little adults, usually changing dose levels according to their weight. Adults and children have “profound anatomical, physiological, and developmental differences,” which translate into differences in how they metabolize drugs — meaning that results from drug trials on adults may not apply to children at all.
Variability is a huge problem for the elderly. John Sloan, a physician who cares for geriatric patients, writes that “the fragile elderly are different from one another in all sorts of ways.”38 He cited kidney function as an example:
As you get older, particularly when you get really old, two things happen. One, kidney function gets worse. So an average eighty-year-old patient will definitely have worse kidney function than she did when she was twenty. But thing number two is that the older you get, the wider the range of kidney function gets. Kidney function becomes heterogeneous. Result: blood levels of kidney-filtered drugs are heterogeneous. One elderly person has kidney function close to that of a normal forty-year-old; another one has awful, barely functioning kidneys. Give a kidney-filtered drug at its textbook dose to the first one, everything is cool. Give it to the second one, the blood level is through the roof and side effects have her flat on her back.
For the fragile elderly, this variability can extend to many organs, making prescribing the right dosage of a drug a huge challenge. As a result, many patients are overmedicated, and serious adverse drug reactions can be dismissed as just another consequence of aging. Compounding the problem is that these patients are usually on several drugs at once, and they can interact with each other to produce new problems. Accurate biomarkers to monitor the therapeutic effects of drugs in this population are desperately needed to achieve the right doses of the right drugs and avoid adverse drug interactions.
At the beginning of this chapter, the democratization of medicine was mentioned as a probable event resulting from molecularly based medicine over the next ten years. But what does this mean? It means that through the availability of inexpensive, accurate, molecular-level diagnostic tests, consumers will be able to get much more definitive information regarding their own health, which will allow them to become much more actively involved in managing it. Patients will no longer be passive recipients of diagnosis and treatment by the medical profession. Health care is moving from hospitals and clinics to the home, into the hands of you, the consumer, as personalized medicine technologies improve self-monitoring and your understanding of your body in health and disease. There are risks and many regulatory issues, but one thing is certain: the democratization and demystification of health care is starting to happen.
There is one large — and unanswered — question in all these conjectures about what may happen over the coming decade: Will all this information make any difference on a population-wide level? Will individuals change their behavior when they can get accurate, predictive information about their health status? This is not an idle question: current evidence suggests that many of us won’t. We all know we should follow a balanced diet low in saturated fats and get more exercise, and smokers have all been told the health risks of cigarettes, but most of us indulge in behaviors that we know are harmful to our health. As health-care editor Paul Cerrato wrote in a commentary for InformationWeek,39 “Most people want to see a doctor only when something breaks down, and then they expect a pill or procedure to make things right, just as they expect their car mechanic to fix their cars. Health care for most Americans is about having someone else ‘make it better,’ not about personal responsibility.” Google’s attempt to launch a personal health-record product, Google Health, was shut down after a few years of low uptake, with the company announcing on its blog, “There has been adoption among certain groups of users like tech-savvy patients and their caregivers, and more recently fitness and wellness enthusiasts. But we haven’t found a way to translate that limited usage into widespread adoption in the daily health routines of millions of people.”40 It is entirely possible that a similar situation will evolve for personalized medicine, in which an elite few who actually use the information available gain considerable benefits but the majority do not. It will be interesting to see how this scenario evolves.
So within the next ten years, personalized medicine will be available to you and will be front and center in the medical scene. It will surely create unrealistic expectations and will be the subject of many portentous editorials saying that the hype far exceeds reality. It will place enormous strains on the medical system as patients become increasingly empowered by real information that they will want acted upon immediately and as doctors try to adjust to a new environment where many of their present skills become outmoded. It may well cause a large number of healthy people to become sick as they try to correct trivial problems they detect. It will cause enormous growth in the health-maintenance industry, which will become the biggest industry of all time. And it will increasingly cater to the desire to change ourselves in ways that make us smarter or better looking or younger. Human evolution won’t be practiced in the Darwinian sense anymore: we’ll do it to ourselves.